Glycolipids revealed recently a number of different immunological properties. Among them, it has been demonstrated that they can act as antigens when presented by CD1 molecules as well as that they can improve the immune response when administrated in combination with a vaccine.
CD1 molecules are a family of highly conserved antigen presenting proteins similar in function to well known Major Histocompatibility Complex (MHC) molecules. While MHC proteins present peptides, CD1 proteins bind and display a variety of lipids and glycolipids to T lymphocytes.
In humans, the various CD1 isoforms are categorized as group I (CD1a, b, c and e) and group II (CD1d) based on sequence similarity [Calabi, F.; Jarvis, J. M.; Martin, L.; Milstein, C., Two classes of CD1 genes, Eur. J. Immunol. 1989, 19, (2), 285-92]. Crystal structures of human CD1a [Zajonc, D. M. et al, Nat. Immunol. (2003), 4, 808-815], hCD1b [Gadola, S. D. et al, Nat. Immunol. (2002), 3, 721-726], hCD1d [Koch, M.; et al Nat. Immunol. (2005), 6, 819-826.] and mouse CD1d (mCD1d) [Zeng, Z.-H. et al Science (1997), 277, 339-345; Zajonc, D. M. et al. J. Exp. Med. (2005), 202, 1517-1526], some in complex with their respective antigens, have revealed how differences in the topology of their respective binding grooves enable them to have a degree of ligand specificity, while maintaining the ability to present a diverse set of antigenic lipids.
In particular, mCD1d revealed an overall fold similar to the MHC class I proteins. The α-chain folds into three domains (α1, α2, and α3) and is closely associated with β2m. The membrane distal α1 and α2 domains form the binding groove, which is composed of an eight-stranded anti-parallel β-sheet floor traversed by two anti-parallel α-helices [Zeng, Z.-H. et al Science (1997), 277, 339-345]. It was further shown that mCD1d could accommodate long lipid tails in two hydrophobic pockets, designated A′ and F′, located in the binding groove. Moreover, the structures of hCD1b and hCD1a demonstrated that CD1, when loaded with antigenic glycolipids, binds the lipid portion in a hydrophobic groove while making available the hydrophilic sugar moiety to make contact with the T-cell receptor.
Mammalian and mycobacterial lipids are known to be presented by human CD1a, CD1b, CD1c and CD1d [Porcelli, S. A. & Modlin, R. L. (1999) Annu. Rev. Immunol. 17, 297-329]. Alpha-galactosyl ceramide (α-GalCer), a lipid found in the marine sponge Agelas mauritianus, has been, to date, the most extensively studied ligand for CD1d. α-GalCer, when bound to CD1d, stimulates rapid Th1 and Th2 cytokine production by Vα14z natural killer T cells (Vα14z NKT cells) in mice, and the human homologue Vα24z NKT cells and can be now considered as a model antigen. However, its physiological significance in mammals remains unclear, as it is enigmatic why an α-galactosyl ceramide of marine origin is such a potent agonist.

Natural Killer (NK) cells typically comprise approximately 10 to 15% of the mononuclear cell fraction in normal peripheral blood. Historically, NK cells were first identified by their ability to lyse certain tumor cells without prior immunization or activation. NK cells also serve a critical role in cytokine production, which may be involved in controlling cancer, infection and possibly in fetal implantation.
Administration of α-GalCer together with immunogenic proteins resulted in an enhanced CD4+ and CD8+ NKT cell response to soluble antigens through interaction with dendritic cells [Ian F. Hermans, I. F. et al., J. Immunol. (2003), 171, 5140-5147]. Administration of α-GalCer also enhanced B lymphocyte responses, eliciting higher frequencies of memory B cells and higher antibody levels in response to booster immunizations [Galli G. et al, PNAS, (2007), 104; 3984-3989]. It has been used to enhance the efficacy of certain peptidic antigens. WO 2005/000348.